Healthcare-associated infections (HAIs) are a leading cause of preventable morbidity and mortality. Prevention of HAIs is a national priority for patient safety and best practice because of their high morbidity, mortality, and cost, incurring over $6.5 billion dollars of healthcare costs each year. Most infections result from common bacteria that normally live on the skin or in the nose and which overcome the body's normal defenses because of invasive medical devices, surgical incisions, or the physiologic effects of hospitalization. Studies in intensive care units (ICUs) indicate that decolonization of patients' skin with chlorhexidine, and nares with mupirocin can prevent many HAIs. However, evidence is lacking about the effectiveness of decolonization in non-ICU settings, where the majority of HAIs occur, and where medical care, risk of infection, patient-to-patient interactions, pathogen transmission, and bathing practices differ considerably from ICU settings. Decolonization is thus rarely used in these settings, despite its potential to meaningfully decrease the HAI rate. The ABATE Infection Trial (Addressing Bioburden while Admitted To Eliminate Infection) will efficiently evaluate the impact of decolonization on HAIs in the general patient population outside ICUs. This cluster- randomized trial will randomize 50 hospitals treating nearly 400,000 patients to evaluate 1) universal daily chlorhexidine bathing to prevent infections from all pathogens, combined with 2) nasal decolonization with mupirocin for known carriers of methicillin-resistant Staphylococcus aureus (MRSA), one of the most common causes of HAIs. While decolonization has been successful in short-stay high risk areas, such as ICUs, this trial will address the much larger problem of HAIs in non-ICU medical and surgical wards. This patient population has typically not been evaluated because the complexity and cost of sufficiently large randomized trials to demonstrate effectiveness have been beyond the reach of conventional hospital-based trials. This trial will provide a critically needed evaluation of decolonization to reduce hospital infection risk and infectious readmissions in nearly all hospitalized patients. It will provide essential information to determine whether routine decolonization through daily bathing with chlorhexidine should become standard practice for 40 million patients hospitalized each year in the United States alone. Alternatively, it will suggest that tailored strategies distinct from those effective in ICU settings are needed for these patient outside ICUs. This trial will also illustrate the strengths of a new model of clinical effectivenes research that quickly and efficiently addresses critical management questions by embedding research into the usual delivery of health care, and using the organizational and informatics strengths of a large hospital system.